Synthesis, In Silico and In Vitro Evaluation for Acetylcholinesterase and BACE-1 Inhibitory Activity of Some N-Substituted-4-Phenothiazine-Chalcones

Abstract

Acetylcholinesterase (AChE) and beta-secretase (BACE-1) are two attractive targets in the discovery of novel substances that could control multiple aspects of Alzheimer's disease (AD). Chalcones are the flavonoid derivatives with diverse bioactivities, including AChE and BACE-1 inhibition. In this study, a series of N-substituted-4-phenothiazine-chalcones was synthesized and tested for AChE and BACE-1 inhibitory activities. In silico models, including two-dimensional quantitative structure-activity relationship (2D-QSAR) for AChE and BACE-1 inhibitors, and molecular docking investigation, were developed to elucidate the experimental process. The results indicated that 13 chalcone derivatives were synthesized with relatively high yields (39-81%). The bioactivities of these substances were examined with pIC₅₀ 3.73-5.96 (AChE) and 5.20-6.81 (BACE-1). Eleven of synthesized chalcones had completely new structures. Two substances AC4 and AC12 exhibited the highest biological activities on both AChE and BACE-1. These substances could be employed for further researches. In addition to this, the present study results suggested that, by using a combination of two types of predictive models, 2D-QSAR and molecular docking, it was possible to estimate the biological activities of the prepared compounds with relatively high accuracy.

Keywords: BACE-1; QSAR; acetylcholiesterase inhibitor; chalcone; docking; in silico.

Figure 1

Claisen–Schmidt condensation reaction in chalcones synthesis. EtONa/EtOH: Sodium ethanolate in ethanol, c-HCl: concentrated hydrochloric acid.

Figure 2

Interactions in the binding pocket of acetylcholinesterase (AChE, complex 1DX6) made by (A) AC4 (observed pIC₅₀: 5.44 ± 0.08), (B) AC12 (observed pIC₅₀: 5.96 ± 0.10).

Figure 3

Interactions in the binding pocket of beta-secretase (BACE-1, complex 5HU1-chain A) made by (A) AC4 (observed pIC₅₀: 6.81 ± 0.09), (B) AC12 (observed pIC₅₀: 6.46 ± 0.05).

Figure 4

The linear regression between observed pIC₅₀ and those predicted from the 2D-QSAR models for inhibitors of (A) AChE and (B) BACE-1.

Figure 5

The linear regression between observed and predicted activities of synthesized chalcone derivatives against (A) AChE (values from AC1–3, AC6–11) and (B) BACE-1 (values from AC1–13).